The invention relates to the object characterized in the claims, i.e., a new process for the production of metal-complex carboxylic acid amides.
Metal-complex carboxylic acid amides are used in a variety of ways in medical diagnosis and treatment. Such compounds and their use as contrast media, primarily in nuclear spin tomography (MRI), are described in, e.g., European Patent Applications No. 0255 471, 0331616, 0430863, 0481526, 0130934 and in International Patent Applications WO 96/02669 and WO 94/28940. Their production is carried out by coupling an amine with the activated carboxylic acid of a complexing agent, whose additional carboxylic acids generally must be present in protected form.
Anhydrides and N-hydroxysuccinimides are frequently used. After the existing acid protective groups are cleaved, the desired metal is introduced.
The following can be cited as the primary drawbacks of this method:
a) Incomplete coupling and associated separating problems of the reaction products. The unreacted amines generally have undesirable pharmacological properties. PA1 b) Incomplete metal incorporation (complexing) into the complexing agent conjugates. An undesirable antidote action (impairing the cardiovascular system) as well as lower effectiveness of the product formed as a diagnostic agent (lower metal content of the contrast medium) are the result. PA1 c) Protective group chemistry always results in additional reaction steps, in which the protective groups must be removed again. In this case, impairment of the pharmacological properties of the desired product can very easily occur. In addition, during the cleavage of the protective groups, large amounts of by-products accumulate that must then be disposed of. Therefore, avoidance of protective groups, especially for processes that are to be used on an industrial scale, is desirable. PA1 d) The yield of the metal-complex carboxylic acid amides that are obtained according to the methods of the prior art is often unsatisfactory. PA1 e) The incorporation of metal, mainly when macrocyclic complexing agents are used, must be performed at high temperatures. This also leads to impairment of the purity of the reaction product. PA1 A stands for the radical of a natural or synthetic amine, and PA1 n stands for numbers 1 to 100. PA1 R stands for a CHX.sup.1 --CO--NH--CHY.sup.1 --(CH.sub.2).sub.f --COOH group, in which X.sup.1 and Y.sup.1, independently of one another, mean a hydrogen atom, a straight-chain or branched C.sub.1 -C.sub.7 alkyl radical, a phenyl or benzyl group, and f means numbers 0 to 9. PA1 Z.sup.1 stands for a hydrogen atom or a carboxyl protective group, after cleavage of the optionally present carboxyl protective groups, are reacted in a way known in the art with a metal oxide or metal salt of an element of atomic numbers 25, 26, 39, 57-71 and 83. PA1 Z.sup.1 has the above-mentioned meaning and Hal stands for chlorine, bromine or iodine, PA1 X.sup.1, Y.sup.1 and f have the above-mentioned meaning.